Graded deletion and virus-induced activation of autoreactive CD4(+) T cells

We have examined factors governing the negative selection of autoreactive C D4(+) T cells in transgenic mice expressing low (HA12 mice) vs high (HA104 mice) amounts of the influenza virus hemagglutinin (HA). When mated with TS 1 mice that express a transgenic TCR specific for the I-Ed-restricted deter minant site 1 (S1) of HA, thymocytes expressing high levels of the clonotyp ic TCR were deleted in both HA-transgenic Lineages. However, through alleli c inclusion, thymocytes with lower levels of the clonotypic TCR evaded dele tion in TS1 x HA12 and TS1 x HA104 mice to graded degrees. Moreover, in bot h lineages, peripheral CD4(+) T cells could be activated by the S1 peptide in vitro, and by influenza virus in vivo. These Endings indicate that allel ic inclusion can allow autoreactive CD4(+) thymocytes to evade thymic delet ion to varying extents reflecting variation in the expression of the self p eptide, and can provide a basis for the activation of autoreactive peripher al T cells by viruses bearing homologues of self peptides ("molecular mimic ry").